Squamous cell cancer in the head and neck (HNSCC) provides fascinating dichotomies because approximately 1/3 of the tumors are caused by HPV and about 2/3 are a result of random mutations. Even though HPV(+) HNSCC presents at a more advanced stage than HPV(-) tumors, the survival are markedly (30-40% at five years) better in patients with HPV(+) HNSCC treated with radiation therapy. Our preliminary data shows that clearance of HPV(+) cancers treated with radiation in our mouse model occurs only the setting of an intact immune response. We hypothesize that HPV(+) cancers are curable due to an immune response that is induced to the tumor cells with radiation therapy. The specific aims are 1) Determine the specific immune cells required for the immune mediated clearance of HPV(+) tumors treated with radiation. Methods include knockout mice lacking components of the immune system, antibody depletion of immune cells, and rescue with splenocyte transfer. 2) Determine the mechanism of radiation induced cell death that promotes clearance of HPV(+) tumors. We will look at markers for apoptosis, autophagy, and necrosis of HPV(+) cells treated with radiation. We will determine whether radiation treated HPV(+) cells undergo apoptosis in an immunogenic context with cell surface exposure of calreticulin 3) Determine treatment modalities that optimize immune mediated clearance of HPV(+) HNSCC. Modalities include optimizing radiation dosing for clearance and determining whether CD40 ligand modulation of the immune system improves tumor clearance. Mice lacking CD40 receptor exhibit uncontrolled growth of HPV(+) tumors similar to mice lacking an immune system, thus showing the importance of CD40 to tumor surveillance/clearance. We will explore whether treatment with CD40 ligand will enhance tumor clearance during radiation treatment. These approaches will allow us to translate our initial observations into potential treatments.